Highlights from Recent Cancer Literature
Journal: Cancer Research (2015)

Mazur and colleagues demonstrated that the BET inhibitor JQ1 cooperated with standard-of-care therapy (gemcitabine) against mouse pancreatic ductal adenocarcinoma (PDAC) cells, resulting in inhibition of MYC, and with inflammatory signals such as STAT3/IL6. Addition of IL6 could counter the JQ1-mediated antitumor response. Recurrence of PDACs occurred after JQ1 monotherapy, with subsequent screens identifying vorinostat (HDAC inhibitor) as synergizing with JQ1—confirmed in vivo in two autochthonous mouse models and two patient-derived xenografts models. Cdkn1c, encoding the cell cycle inhibitor p57, highly induced genes when vorinostat was combined with JQ1. Inactivation of Cdkn1c resulted in decreased efficacy of the JQ1-vorinostat combination. This study provides a preclinical rationale to test BET inhibition and HDAC inhibition in PDAC and identifies p57 as mediating potent antitumor responses.Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 2015;21:1163–71.Sonic Hedgehog (SHH)-dependent basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma were initially identified in the inherited human disorder Gorlin's syndrome. One limitation to understanding the mechanistic role SHH plays is that tumors rapidly lose SHH dependence when grown in vitro. Zhao and colleagues now characterize a series of mouse medulloblastoma cell lines that retain SHH dependence. They identify two novel mechanisms of resistance to clinical SMO inhibitors. Mutations in the SHH signaling component Sufu, which acts downstream of Smo, allow activation of SHH signaling independently of SMO. More importantly, they show that activation of RAS/MAPK-dependent signaling, driven primarily by FGF, also drives resistance and may be relevant to human medulloblastoma. This novel mechanism of SMO inhibitor resistance actually represses SHH signaling and drives tumor growth and metastasis in a SHH-independent manner.Zhao X, Ponomaryov T, Ornell KJ, Zhou P, Dabral SK, Pak E, et al. RAS/MAPK activation drives resistance to Smo inhibition, metastasis, and tumor evolution in Shh pathway-dependent tumors. Cancer Res 2015;75:3623–35.Loss of histone H3K36 trimethylation is associated with active gene transcription. Based on observations in yeast that loss of Set2 (a SETD2 ortholog and sole methyltransferase for H3K36me3) is synthetically lethal with the loss of Wee1, Pfister and colleagues demonstrate that H3K36me3-deficient cancers are hypersensitive to WEE1 inhibition by AZD1775 or knockdown of WEE1. In SETD2-deficient cells, which are H3K36me3 deficient, WEE1 inhibition blocked DNA replication, inducing replication stress and collapse of stalled replication forks. This profound synthetic lethal phenotype was attributed to reduced levels of the ribonucleotide reductase subunit RRM2, leading to depletion of deoxyribonucleoside triphosphate and S-phase arrest. Inhibition of WEE1 in tumor xenografts of SETD2-deficient cells resulted in increased replication stress, increased apoptosis, and reduced tumor size. This synthetic lethal interaction has therapeutic implications for glioblastoma and other cancers with loss of H3K36me3.Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M, Orlando G, et al., Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 2015;28:557–68.Using a multi-platform integrative analysis, Yan and colleagues characterized profiles of long noncoding RNAs (lncRNA) in 5,037 tumor samples across 13 cancer types. The expression of many lncRNAs was deregulated in cancers relative to corresponding normal tissues. Sixty percent of these alterations were cancer type specific, resulting from copy number changes and lncRNA promoter hypermethylation. Many previously identified cancer-associated SNPs actually localized within the loci of lncRNAs. They established a virtual screening protocol to prioritize lncRNA that could be tested functionally. In breast cancer, cancer-associated alterations in 19 lncRNAs were associated with patient survival. Focusing on one of these, they also noted overexpression in ovarian cancer. Knockdown of this lncRNA significantly reduced the growth of breast and ovarian cancer cells in vitro and in vivo.Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell 2015;28:529–40.One mechanism driving resistance of glioblastoma (GBM) cells to the alkylating agent temozolomide utilizes O-6-methylguanine-DNA methyltransferase (MGMT) to repair temozolomide-induced DNA damage. Interestingly, patients deficient in MGMT survive longer despite developing temozolomide resistance. Murphy and colleagues studied how the gap junction protein connexin 43 (Cx43, GJA1) enhances temozolomide resistance in GBM. Temozolomide sensitivity and Cx43 expression correlated inversely in GBM cells and GBM stem cells. In MGMT-deficient GBM, Cx43 levels and survival also correlated inversely. A C-terminal peptide mimetic of Cx43 sensitized MGMT-deficient and temozolomide-resistant GBM cells to temozolomide. Combining the peptide mimetic with temozolomide blocked AKT/mTOR signaling, inducing autophagy and apoptosis. Thus, Cx43 might serve as a biomarker to predict survival, and treatment with a Cx43 inhibitor might enhance temozolomide response in GBM patients.Murphy SF, Varghese RT, Lamouille S, Guo S, Pridham KJ, Kanabur P, et al. Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. Cancer Research; Published OnlineFirst November 5, 2015; doi:10.1158/0008-5472.CAN-15-1286.Although interpatient heterogeneity is well recognized in prostate cancer, a robust molecular subclassification is needed for applied therapeutics. Mateo and colleagues report the results of a phase 2 trial of the PARP inhibitor olaparib in previously treated patients with metastatic prostate cancer. They hypothesized that individuals with somatic alterations in DNA repair genes identified at time of therapy resistance would respond to olaparib, as previously reported in men with germline BRCA2 mutations. Antitumor responses for &gt;6 months were observed in 33% of patients, with next-generation sequencing identifying somatic homozygous deletions and/or deleterious mutations in DNA repair genes, including BRCA1/2, ATM, CHEK2, and Fanconi anemia genes. Additional studies are needed to validate the frequency of this biomarker in patients with advanced prostate cancer and to assess impact of PARP-inhibitor sensitivity on long-term survival.Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.